Macrophages are essential components of the human immune system, which can perform different functions in the body’s immune response, such as regulating apoptosis, phagocytosing of pathogens, remodeling the extracellular matrix, activating other immune cells, and so on. Under various stimuli, macrophages can polarize into two phenotypes, M1 and M2 (Wynn et al., 2013; Koelwyn et al., 2018). Among the two phenotypes of macrophages, classical M1-polarized macrophages can promote the secretion of pro-inflammatory factors, promote the antibacterial reaction, and alternative M2-polarized macrophages [activated by Interleukin-4 (IL-4) and Interleukin-13 (IL-13)], which are generally considered to have the immunosuppressive effect (Wang et al., 2016a). MSCs inhibit macrophages activation and transform the M1 phenotype to the M2 phenotype.

Dendritic cells are individual antigen-presenting cells. They are heterogeneous population of leukocytes with different subpopulations, which are responsible for driving specific immune responses and initiating and modulating adaptive immune responses (Lee and Radford. 2019).

MSCs are allowed to mediate immune responses by regulating T cells’ activity. T cells are immune cells that originate from the BM and differentiate and mature in the thymus gland. T cells are essential for the body’s immune response, maintenance of homeostasis, maintenance of immune memory, and recognition of pathogens (Kumar et al., 2018).

B cells are derived from stem cells of BM, mainly located in human lymph nodes and spleen. B cells can involve in regulating the immune response, which is related to their ability to produce antibodies. Mature B cells may become activated B cells after being stimulated by antigen, and then differentiate into plasma cells to secrete and synthesize antibodies, to perform humoral immunity (Mauri and Bosma. 2012; Zhang et al., 2012).

NK cells, also known as natural killer cells, are critical immune cells produced by the body, and they are involved in hypersensitivity reactions. NK cells have many receptors that receptors tightly regulate the activity of NK cells, enabling them to distinguish between “normal” and “dangerous” cells (Morvan and Lanier. 2016; Hodgins et al., 2019).

Myocardial infarction (MI) is a disease caused by severe narrowing of the coronary arteries and a dramatic reduction or interruption of the blood supply, which leads to severe acute ischemia in the myocardium and ischemic necrosis. Myocardial ischemia over a long period of time can lead to myocardial cell death, severe angina pectoris, arrhythmias, and other symptoms, which could be life-threatening in severe cases.

MSCs are able to reduce cardiac dysfunction through immunomodulatory effects. The reason why MSCs can treat heart disease may be due to promoting the increase in the number of M2 macrophages. In the mice MI model, MSCs were injected into mice with BM-derived macrophages and found that MSCs could reduce M1 phenotypic markers (IL-6, IL-1β) and increase M2 phenotypic markers (IL-10, IL-4), and facilitated the recovery of cardiac function (Cho et al., 2014). Interleukin-33 (IL-33) is the tissue-derived nuclear cytokine from the IL-1 family, its function is to release alarm signals in case of cell damage or tissue damage. It targets mast cells, Tregs, NK cells, neutrophils, and macrophages in the body, making it a vital important immunomodulatory molecule (Cayrol and Girard. 2018). MSCs transfected with IL-33 were co-cultured with T cells and macrophages, and the proliferation of T cells and polarization of macrophages were observed. The experiments showed that IL33-MSCs decreased T cells proliferation, and enhanced the polarization of M1 phenotype to M2 phenotype, and the myocardial fibrosis, inflammation, and cardiac function recovered better with IL33-MSCs (Chen et al., 2019b).

In addition to IL-33, IL-10 is also an important immunomodulatory factor. IL-10 is a multipotent cytokine with properties that prevents host damage by limiting the immune response of pathogens and exerts immunosuppressive or immunostimulatory effects in various cells (Saraiva and O'Garra. 2010). MSCs are able to perform immunomodulatory functions by regulating IL-10, IL-10-transfected MSCs were injected into MI mice and found that IL-10-transfected MSCs enhanced cell viability and increased IL-10 secretion, the infarct size, myocardial injury and apoptosis were reduced, and systemic and local inflammation were reduced (Meng et al., 2018).

MSCs play a role in tissue repair of cardiovascular diseases. Studies have shown that after MI, MSCs can differentiate into endothelial cells or cardiomyocytes and exert their immunomodulatory effects, such as alleviating tissue damage and promoting tissue repair by inhibiting neutrophil infiltration. Alternatively, tissue repair is achieved by altering the distribution of effective immune cells and recruiting M2 macrophages to the vicinity of damaged tissue. In the murine model of MI, injection of MSCs significantly decreased the M1 phenotype of macrophages, decreased the expression of Interleukin-1β (IL-1β) and IL-6, increased the expression IL-10, and increased the alternating activation of monocytes/macrophages. MSCs may repair the myocardium through IL-10-mediated infiltration of pro-inflammatory macrophages to anti-inflammatory macrophages at the site of infarction (Dayan et al., 2011). MSCs were injected in the porcine model of heart failure combined with MI and were found to exhibit enhanced viability and promote vascular regeneration by activating Tregs and reducing inflammatory cells (Liao et al., 2019).

However, single MSCs therapy tends to have low delivery rates. In the rat model of MI, it was found that combined delivery of MSCs and MSCs-derived exosomes were able to achieve more efficient anti-inflammatory and vascular tissue repair than MSCs therapy by decreasing the expression of inflammatory factors such as IL-6 and TNF-α and increasing the expression of Recombinant Stromal Cell-Derived Factor 1 (SDF-1) (Huang et al., 2019).

MSCs and their derived materials are emerging in the treatment of MI as well. Exosomes of porcine cardiac adipose tissue-derived MSCs (cATMSC) loaded onto a three-dimensional scaffold designed from decellularized heart tissue and injected into pigs after MI, found to reduce macrophage and T cell infiltration in the damaged myocardium and increase vascular density and tissue remodeling (Monguió-Tortajada et al., 2021). Researchers coated the cell membrane of MSCs on PLGA particles loaded with MSCs secretions to create a particle called synMSCs and injected it into mice with acute myocardial infarction (AMI), and found that synMSCs-treated mice were able to express MHC I molecules that allowed them to avoid allogeneic recognition by the immune system, thereby modulating the body’s innate immune response and enhancing their attachment to cardiomyocytes and promoting their survival by secreting adhesion factors (such as SDF1) (Luo et al., 2017). Vineeta Sharma and his colleagues found that 5-Aza loaded protein nanoparticle with MSCs encapsulated hydrogels may support in vitro MSC proliferation, migration and angiogenesis in rat MI model, and the hydrogels could alleviate ventricular remodeling after myocardial infarction by secreting immunoregulatory factors (Sharma et al., 2021). The addition of MSCs -derived exosomes to alginate hydrogel revealed that the delivery of exosomes incorporated in alginate hydrogel (sEVs-Gel) increased residence time in the heart, and promoted the polarization of macrophages from M1 phenotype to M2 phenotype more than exosomes treatment alone, promoted scar tissue repair and vascular regeneration (Lv et al., 2019). Some clinical treatments with MSCs have shown encouraging results. For example, in a clinical study of patients with chronic ischemic heart disease, patients were found to reduce myocardial infarct size, increase LVEF and promote recovery of cardiac function after intravenous administration of MSCs (Kanelidis et al., 2017).

Heart failure is a progressive disease, the syndrome that occurs when the cardiovascular diseases progress to a more severe stage. It is usually caused by structural and functional changes in the myocardium due to organic or functional lesions of the heart, which impairs the filling degree and ejection fraction capacity of the ventricles. Furthermore, immune activation and inflammatory responses play an essential role in the course of heart failure.

The therapeutic effect of MSCs on heart failure is mainly based on their ability to regulate the body’s innate and adaptive immunity. Peripheral blood mononuclear cells were isolated from fresh blood samples of patients with end-stage heart failure and co-cultured with MSCs derivatives. The results showed that MSCs had a strong immunosuppressive ability and inhibited lymphocyte proliferation and antibody production in vitro, and plasma cells from patients with end-stage heart failure had high IgG3 production, in vitro experiments showed that MSCs could inhibit IgG3 production, thereby preventing ventricular remodeling after MI and slowing the progression of heart failure (van den Hoogen et al., 2019). CD4 is generally expressed on the surface of human T cells, while Th1 cells in CD4 have a role in humoral immunity (Loo et al., 2018). CD4/CD8 is an important indicator of immune regulation (Overgaard et al., 2015). Co-transplantation of MSCs and pluripotent stem cell-derived cardiomyocytes into mice revealed that MSCs directly affected activated lymphocytes through cell-to-cell contact, thereby decreasing the CD4/CD8 ratio and the proportion of Th1-positive cells among CD4-positive cells and the secretion of various inflammation-related cytokines. Moreover, this pathway could increase the number of cardiomyocytes, enhance myocardial contraction (Yoshida et al., 2020). Denise Philipp and his colleagues studied the effects of bone marrow-derived preconditioned MSCs on hypertrophy-induced pluripotent stem cell-derived cardiomyocytes (iPS-CM), and found that MSCs could participate in immune regulation by secreting cytokines such as IFN-γ and IL-1β, and trigger regression of hypertrophy in iPS-CM in a VEGF-dependent manner, so MSCs therapy may inhibit cardiac hypertrophy (Philipp et al., 2021).

Some clinical studies have shown that MSCs is a new target for the treatment of heart failure. After MSCs injected into patients with chronic heart failure, a momentous decrease in CD4-positive and NK cells was found, a large improvement in left ventricular end systolic volume (LVESV) and LVEF was observed. In this study, MSC therapy was safe, and caused immunomodulatory effects (Butler et al., 2017). Intravenous infusion of UC MSCs in patients with chronic heart failure revealed that UC MSCs could participate in the regulation of adaptive immunity and myocardial remodeling in the body by secreting hepatocyte growth factor (HGF), inhibit T-cell proliferation, and reduce the proliferation of Th 1, Th 2, and cytotoxic T cells (Bartolucci et al., 2017).

MSCs derived materials are also a new target for the treatment of heart failure in recent years. Human amnion-derived stem cells (hAM-MSCs) dressing is a novel MSC-derived material with good potential for clinical application. After administration of hAM-MSCs dressing to mice with ischemic cardiomyopathy, it was found that the dressing could improve myocardial remodeling by promoting the secondary release of paracrine factors from endogenous cells and promoting the polarization of the M1 phenotype to the M2 phenotype of macrophages. So, hAM-MSCs dressing can slow down the development of heart failure (Fields et al., 2021). Pura-Matrix hydrogel with MSCs applied to mouse epicardium after MI, found that it could inhibit the development of inflammation, promote the formation of myocardial capillary, reduce interstitial fibrosis, improve cardiac function and alleviate the progression of heart failure by secreting cytokines such as IL-10 (Ichihara et al., 2018). Researchers seeded MSCs and macrophages into a polycaprolactone scaffold and filled it with MSCs-derived exosomes, found that this novel MSCs-derived material increased the wound healing properties and type I collagen of MSCs and improved the M2 phenotype of macrophages, thus this exosome-rich bio scaffold is an effective strategy to restore contractility of myocardial scars (Chachques et al., 2021). Both MSCs and their derived materials can play a role in the treatment of heart failure by secreting immune factors and regulating immune cells (Figure 3).

Atherosclerosis is a chronic vascular inflammatory disease. That is the cause of coronary heart disease. Atherosclerotic lesions are associated with macrophages, T cells and other immune response cells (Hansson and Hermansson. 2011).

Because of their immunomodulatory and tissue regenerative capabilities, MSCs are well-positioned to treat atherosclerosis, And the therapeutic effect of MSCs on atherosclerosis is mainly achieved by regulating macrophages. As we all known, abnormal lipid metabolism can lead to endothelial dysfunction and the secretion of adhesion factors, leading to the recruitment of macrophages to form foam cells, promoting atherosclerotic plaque formation. Macrophages secrete anti-inflammatory factors, such as IL-10, TGF-β, and promote blood vessel regeneration and tissue remodeling and repair (Adutler-Lieber et al., 2013). Therefore, the treatment of atherosclerosis with MSCs is mainly completed by regulating macrophages, and some immune factors also play a role in this process. For example, IL-6 is produced in response to infection and tissue injury and contributes to host defense by stimulating the acute phase response, hematopoiesis, and immune response. Persistent dysregulation of IL-6 synthesis plays a pathological role in chronic inflammation and autoimmunity (Tanaka et al., 2014). Human-induced pluripotent stem cells (iPSC-MSCs) were intravenously administered to ApoE ^−/−mice on an HFD for 12 weeks, and iPSC-MSCs were found to notably reduce plaque size and make the macrophages in the plaques lower than those in the controls. Furthermore, iPSC-MSCs reduced inflammation by reducing serum levels of inflammatory cytokines, such as TNF-α and IL-6, thereby treating atherosclerosis (Shi et al., 2018b). Skin is an ideal source of MSCs supply, and in the ApoE ^−/− mice model, skin-derived MSCs(S-MSCs) were found to migrate into atherosclerotic plaques and selectively adhere in the vicinity of macrophages. Furthermore, it reduced the release of the pro-inflammatory cytokine TNF-α and increased the expression of anti-inflammatory factor IL-10 in atherosclerotic plaques, resulted in the regulation of macrophages function and inhibition of atheromatous plaque formation (Li et al., 2015b). MSCs-derived exosomes are considered a new target for the treatment of atherosclerosis. MSCs-derived exosomes injected into ApoE^−/− mice and MSCs-derived exosomes were found to promote polarization of the macrophages M2 phenotype and reduce plaque size and macrophages infiltration via miRNA-21a-5p (Ma et al., 2021).

In addition to macrophages, Treg and T cells are also able to play a role in the treatment of MSC. TGF-β1 could produce an immune response when it is activated, and Tregs can suppress proximal immune cells by activating Glycoprotein -A repetitions predominant (GARP) -mediated activation of potential TGF-β1 acting on their surface with integrin αVβ8. Treatment of atherosclerotic mice with MSCs revealed increased secretion of anti-inflammatory cytokines such as TGF-β1 and IL-10 and TGF-β1 could be involved in MSC-mediated changes in the number of CD4⁺CD25⁺ forkhead box P3 (FOXP3) ⁺Tregs and NK cells, and reduce their proliferation, this resulted in the regulation of host adaptive immunity (Li et al., 2017; Liénart et al., 2018). Mice were injected with MSCs after low-density lipoprotein (LDL) knockout and fed a high-fat diet (HFD), which induced atherosclerosis, it was found that the number of T cells reduced after MSCs treatment, the serum CCL2 level decreased, the lesion in the aortic root reduced, the number of macrophages at the lesion site decreased, and serum cholesterol reduced. It was shown that treatment with MSCs greatly reduced dyslipidemia and treated atherosclerosis in mice (Wang et al., 2015).

MSCs are capable of exerting immunomodulatory and immunosuppressive effects through some signaling pathways. Culture media for ADMSCs, like MSCs, can reduce the expression of cell adhesion factors by inhibiting the mitogen-activated protein kinase (MAPK) and NF-κB pathways and reduce the accumulation of macrophages in the vessel wall by inhibiting MAPK and NF-κB pathways. The κB pathway decreases LPS-induced M1 marker expression and increases M2 marker expression through activation of the STAT3 signaling pathway (Takafuji et al., 2019) (Figure 4).

After MI, timely reperfusion treatment can reduce the infarct area, but symptoms such as arrhythmia and myocardial contractile dysfunction often occur after reperfusion therapy, thus leading to myocardial ischemia-reperfusion injury (MIRI) (Cohn et al., 2000). Infiltration of inflammatory cells occurs after myocardial ischemia/reperfusion, allowing the progression of MIRI toward inflammatory injury.

Toll-like receptor 2 (TLR2), the most widely expressed member of the TLR family, is the type I transmembrane protein that acts as a pattern recognition receptor, recognizes and binds to several pathogen-associated molecular patterns, and triggers a cascade of signaling that leads to the release of mediators of inflammation, thereby initiating an innate immune response. TLR2 is associated with inflammation and myocardial dysfunction after MIRI, knockdown of MSCs-derived exosomes of TLR2 could improve myocardial recovery from immunomodulation and promote the release of vascular growth factors, thereby protecting cardiac function (Ma et al., 2018). Neutrophils play an important role in the development of MIRI. MSCs were injected in MIRI model rats and were found to be able to initiate an immune response and improve cardiac function in rats after MIRI by enhancing M2 macrophages-induced efferocytosis of apoptotic neutrophils (Zhang et al., 2020a). CD73 can convert Adenosine monophosphate (AMP) into adenosine, thereby inhibiting T-cell activation. In the rat model of MIRI, MSCs were injected into the damaged myocardium and found to mediate the activity of CD73 and attenuate the infiltration of innate immune cells, thereby protecting cardiac function (Shin et al., 2018).

MSCs injection into mice with AMI revealed that MSCs-derived exosomes had profound immunomodulatory effects on DCs and monocytes or macrophages, and exosomes from highly expressed miRNA-181 MSCs created an anti-inflammatory environment, enhanced Tregs polarization, and significantly improved ischemia-reperfusion through downstream c- Fos proteins cardiac function and infarct size in mice with impaired perfusion (Wei et al., 2019). MSCs-derived exosomes could promote the conversion of macrophages from M1 to M2 phenotype by secreting miRNA 182-a and downregulating TLR4, thereby reducing the infarct size and decreasing the level of inflammation in the ischemic myocardium of mice with MIRI (Zhao et al., 2019). The MSCs-derived exosomes were modified with monocyte mimics to form monocyte mimic-bioinspired MSC-EVs (Mon-Exos), which found to have better targeting to the damaged myocardium. In a rat MIRI model, it promoted vascular endothelial repair and modulated macrophage subsets, thus resulted a significant improvement in cardiac function (Zhang et al., 2020b).

Heart transplantation cause MIRI due to procurement and long transplantation times, and although MSCs are cardioprotective, there are still many limitations to this treatment. To address the limitation that MSCs are difficult to transport and store, the researchers treated mice hearts with ischemic cryopreservation followed by the use of a preservation solution, It was found that MSCs-CMs or MSCs-EVs in the preservation solution reversed the adverse effects of long-term frozen ischemia on the donor heart and achieved protection of the donor heart by inhibiting the secretion of pro-inflammatory factors such as IL-1β and IL-6 (Wang et al., 2020). Therefore, both MSCs and MSCs-derived exosomes can inhibit MIRI by exerting their immunoregulatory functions.

Dilated cardiomyopathy is defined by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery diseases or abnormal loading conditions. And it is one of the causes of heart failure (Japp et al., 2016). The expression of some genes is extremely important for the immunomodulatory process of MSCs, and MSCs are able to modulate the expression of some cytokines by regulating the expression of genes, thus enabling MSCs to play a role in the treatment of diabetic cardiomyopathy. In the rat model of dilated cardiomyopathy, double overexpression of miR-19a and miR-20a in human-induced iPSC -MSCs was able to suppress the inflammatory response and promote the recovery of cardiac function in rats with dilated cardiomyopathy by inhibiting the secretion of TNF-α/IL-1ß (Sheu et al., 2021). MSCs were injected intravenously into rats with diabetic cardiomyopathy and found to secrete cytokine PGE2 through paracrine action, thereby immunomodulating diabetic cardiomyopathy rats, reducing myocardial fibrosis and alleviating cardiac function (Jin et al., 2020). MSCs-derived exosomes were able to improve the myocardial inflammatory microenvironment in mice with dilated cardiomyopathy by significantly reducing M1 macrophages in the blood and heart and promoting the conversion of macrophages from the M1 phenotype to the M2 phenotype, promoting the recovery of cardiac function (Sun et al., 2018).

Chronic chagas disease cardiomyopathy, a highly fatal inflammatory cardiomyopathy associated with the patient’s innate immune response, mainly characterized by high expression of the pro-inflammatory cytokine Th1 T cells, hypertrophy of cardiomyocytes and prominent fibrosis in the cardiac lesion region (Cunha-Neto and Chevillard. 2014). MSCs may treat Chronic chagas disease cardiomyopathy by regulating the secretion of inflammatory factors. The study showed that MSCs caused inhibition of cardiac inflammation and fibrosis and reduced the expression levels of TNF α, IL-1β, IL-6, and IFN-γ in the mice model of chronic chagas disease cardiomyopathy, and indicated that MSCs had rich potential to treat chronic Chagas disease cardiomyopathy (Souza et al., 2017). MSCs that overexpress granulocyte colony-stimulating factor (MSC G-CSF) could modulate the adaptive immunity of the body by regulating Tregs, leading to the treatment of inflammatory cardiomyopathy caused by chronic Chagas disease (Silva et al., 2018).

Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction that causes cardiogenic shock and death (Cooper. 2009). Researchers found that FM-MSCs-treated mice with experimental immune myocarditis had significantly fewer infiltrating Th17 cells and a significantly lower proportion of Th1 cells. It was found that FM-MSCs could improve the body’s immunity by suppressing Th1/Th17, thereby treating experimental immune myocarditis (Ohshima et al., 2012). In addition, MSCs could reduce the severity of experimental immune myocarditis by releasing HGF and inhibiting the expression of IL-2, IL-6 in the myocardium (Okada et al., 2007). Injected MSCs overexpressing IL-10 in a mouse model of autoimmune myocarditis and found that MSCs were able to reduce the inflammatory level of the heart and the degree of myocardial fibrosis by delivering IL-10, thereby preventing and treating overactivated immune system from attacking cardiomyocytes (Shao et al., 2020). Coxsackievirus B3(CVB3) can induce myocarditis. Co-cultured of MSCs with CVB3-infected HL-1 cardiomyocytes revealed that MSCs reduced the CVB3-induced CD4⁺ and CD8⁺ T cells activation in a nitric oxide (NO)-dependent way and required IFN-γ priming (Van Linthout et al., 2011) (Figure 5; Table 2).